Increasing evidence suggests that infectious agents can affect the development of autoimmune diseases. Viruses have been most often implicated in the etiology of autoimmune diseases, although bacteria may also be involved: streptococcal infection may lead to rheumatic fever and myocarditis, Mycoplasma arthriditis or its toxins can cause arthritis in mice or rats, and arthritis has also been associated with reactivity to mycobacterial antigens, both in humans and rats. However, several reports indicate that viruses and bacteria may also enhance the natural propensity of mice to become resistant to an autoimmune disease. Thus, non-obese diabetic mice infected with lymphocytic choriomeningitis virus become resistant to the development of insulin-dependent diabetes mellitus, and mice infected with lactic dehydrogenase virus are refractory to the development of experimental autoimmune encephalomyelitis (EAE). Similarly, bacteria may also be involved in conferring resistance to autoimmune diseases, as demonstrated in a previous study by the present inventor (Lehman and Ben-Nun, 1992).
EAE is an autoimmune disease of the central nervous system (CNS) that is caused by CD4.sup.+ T lymphocytes specific for myelin antigens, such as MBP or PLP (Ben-Nun and Lando, 1983). In SJL/J mice, the disease can be induced by injecting the animals with CNS homogenate, MBP or PLP, or with peptides derived therefrom (Raine, 1984). However, disease induction is dependent on the presence of immunoadjuvant in the inoculum. Mt is routinely used as the immunopotentiating agent in the induction of experimental autoimmune diseases. However, its mode of action in enhancing the development of the disease remains unclear. Although controversial data were obtained, there is an indication that Mt can also protect Lewis rats against the induction of an autoimmune disease (Lisak and Kies, 1968; MacPhee and Mason, 1990; Hempel et al., 1985). The inventor recently analyzed the effect of Mt and other bacteria on EAE in SJL/J mice, and observed that mice pre-exposed to Mt acquired long-lasting resistance to EAE, even when the bacteria were administered as an aqueous preparation, rather than as an emulsion in IFA. This study clearly demonstrated that Mt can not only promote the development of EAE, but can also protect against the disease, depending on the time of exposure to the bacteria (Lehman and Ben-Nun, 1992). Because effective protection was obtained with non-pathogenic bacterial preparations (heat-killed bacteria), it was speculated that immunity against a particular component(s) of Mt may be sufficient to confer resistance against induction of an autoimmune disease. Accordingly, it was recently demonstrated by the inventor that PPD is the major fraction of Mt which confers on mice resistance to induction of EAE (Ben-Nun et al., 1993). The protection observed following immunization with PPD was not a simple consequence of a non-specific effect on the immune balance, as other immunogens, both bacterial and non-bacterial, had only marginal or no protective effect.
It should be noted that EAE is the well established and widely accepted animal model for studying the effects of various agents which may be implicated in human autoimmune diseases in general, and particularly multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus and graft-versus-host disease. Thus, an agent found to be capable of eliciting a protective effect against EAE in animals such as mice or rats, is also considered to be an agent capable of eliciting protection against autoimmune diseases in humans.